Understanding Individualized Genetic Interventions as Research-Treatment Hybrids

Abstract

Until recently, medicine has had little to offer most of the millions of patients suffering from rare and ultra-rare genetic conditions. But the development in 2019 of Milasen, the first genetic intervention developed for and administered to a single patient suffering from an ultra-rare genetic disorder, has offered hope to patients and families. In addition, Milasen raised a series of conceptual and ethical questions about how individualized genetic interventions should be developed, assessed for safety and efficacy, and financially supported. The answers to these questions depend in large part on whether individualized therapies are understood as human subjects research or clinical innovation, different domains of biomedicine that are regulated by different modes of oversight, funding, and professional norms. In this article, with development and administration of the drug Milasen as our case study, we argue that at least some individualized genetic therapies are not, as some have argued, either research or treatment. Instead, they are research-treatment hybrids, a category that has both epistemological and pragmatic repercussions for funding, ethics oversight, and regulation.

INTRODUCTION

Taken collectively, rare genetic diseases are common. In the U.S., approximately 7,000 different rare conditions (diseases that affect fewer than 200,000 people) (1) taken in aggregate affect as much as 10 percent of the population. (2) Even ultra-rare diseases, a subcategory with no official regulatory definition that has been described as comprising conditions known to affect 30 or fewer individuals, are thought to afflict millions worldwide. (3) For a long time, medicine has had little to offer these patients beyond, in some cases, a genetic diagnosis, which can refine health surveillance. But the development in 2019 of Milasen, the first genetic intervention designed for and administered to a single patient suffering from an ultra-rare genetic disorder, has offered some hope to patients and families.

Milasen is an antisense oligonucleotide (ASO)—a short nucleic acid molecule that in this case is intended to change the splicing of a disease-causing gene. (4) Along with gene addition and gene editing approaches, ASOs like Milasen offer a pathway for realizing the promise of precision medicine for people with the rarest of genetic conditions. In addition to hope for patients and their families, however, the advent of extremely individualized genetic therapiesⁱ raises a series of conceptual and ethical questions about how these interventions should be developed, assessed for safety and efficacy, and financially supported.(5)(6) The answers to these questions depend in large part on whether use of individualized therapies is understood as human subjects research or clinical innovation: two different domains of biomedicine with different modes of oversight, funding, and professional norms [see figure 1]. Here, with development and administration of the drug Milasen as our case study, we argue that at least some individualized genetic therapies are not solely research or solely treatment; they are both. We call them research-treatment hybrids – a novel category that has both epistemological and pragmatic repercussions for funding, ethics oversight, and regulation.

FIGURE 1:

Research and treatment features of the Milasen case

THE MILASEN CASE STUDY

At six years old, Mila Makovec was diagnosed with an extremely rare, rapidly progressive neurological disorder called Batten’s disease. In less than a year, a team of 48 clinicians and researchers led by Dr. Timothy Yu of Boston’s Children’s Hospital had identified the specific genetic variant causing Mila’s condition—a retrotransposon that disrupted RNA splicing.(7) Mila was the first known case of Batten’s disease with this particular genetic cause. (4) Yu’s research team designed an antisense oligonucleotide (ASO) to correct her unique splicing defect, testing the effectiveness of the ASO in fibroblasts cultured from the patient and assessing its potential toxicity in rats. Just a month later, in early 2018, the team sought and received permission from the Food and Drug Administration to begin administering the ASO to Mila. Over the next two years, following repeated administration of Milasen, the patient’s family reported a decrease in Mila’s seizure frequency. (4) While Milasen improved Mila’s quality of life, it did not cure her disease. Mila Makovec died in February 2021 at the age of 10.

The oversight and regulatory approaches applied to Milasen were a complex and alternating mix of human subjects research and clinical innovation processes. To develop the ASO, researchers needed to collect blood and skin cells from Mila. This aspect was understood as human subjects research, overseen by the Boston Children’s Institutional Review Board (IRB). Yet at the point of administration, Milasen appears to have been treated as a clinical intervention, albeit a novel one. Although Mila’s doctors obtained the concurrence of the IRB chair, Mila received the intervention under an expanded access approval from the FDA, an exception to usual FDA regulations for patients not eligible for an ongoing clinical trial. Access in these cases is driven by clinical need, and patients under an expanded use approval are not research subjects. But in the Milasen case, there was no clinical trial—the single expanded access patient was the only person receiving the intervention, a fact that was clear to the FDA.

Funding for development of Milasen was also a research-treatment mix, coming from the Boston Children’s Hospital Translational Research Program and the Mila’s Miracle Foundation, a charity founded by the patient’s family to pursue a treatment for Mila and other children with rare diseases. The researchers and clinicians involved in the development and administration of Milasen understood its importance for other clinicians, researchers, and patients, writing a manuscript for the New England Journal of Medicine describing the case and stating that they hoped it would serve as “a possible template for the rapid development of patient-customized treatments.”(4)

In the time since Yu’s team reported their work, Milasen has become a model for new individualized genetic interventions, developed to treat specific patients using potentially replicable intervention-development pathways. There are three main types of genetically-targeted, individualized interventions in development: approaches similar to Milasen that seek to impact splicing or gene expression using synthetic strands of DNA or RNA; “gene addition” approaches that use viral vectors or other delivery methods to add a functional copy of a gene in patients with loss-of-function mutations (8); and “gene editing” approaches that use CRISPR or other technologies to edit or alter patients’ genes. (9) The hope is that all three types of novel interventions can be tailored to rare genetic variants that affect a single or a small number of patients, many of them children. (10)

A number of scientific questions are raised by Milasen and other individualized genetic interventions. Are they safe and effective? Can early examples serve as models for subsequent patients, yielding well-defined intervention development pathways? These questions quickly lead to oversight, ethics, and regulatory ones. Can such pathways be reviewed through existing oversight and regulatory systems, or must each intervention be assessed as a new investigational drug or biologic? When discussing these interventions with patients, should clinicians wear their researcher “hat,” emphasizing risks and working to address any therapeutic misconception on the part of the research subject, or should they work as clinicians pursuing innovation with patients who they genuinely believe might benefit from the interventions? Who should fund this work? Who should oversee it? At what point is there sufficient evidence to consider the intervention safe and effective? While often not posed explicitly, the answers to such questions hinge on whether individualized genetic interventions are understood to be treatment or clinical research.

If their development and administration is human subjects research, they will be overseen by research ethics committees such as Institutional Review Boards (IRBs) in the U.S., with stopping rules, conflict of interest requirements, research-focused informed consent procedures, and other features designed to protect participants from harm while enabling the systematic accumulation and dissemination of knowledge. (11) If they are instead understood as novel clinical treatments, then risk-benefit analyses will reflect patient-clinician negotiated goals of care and ethical guidance, and oversight will be drawn from clinical ethics, rather than the formal, prospective review processes applied to research. If they are research, their development and administration might be supported by biomedical research funders, as well as government bodies that support basic science, translational, and clinical research. If they are treatment, patients and their families will likely provide the majority of the financial support needed for their development and administration, although insurance companies will increasingly be petitioned to cover them.

MILASEN AND THE TREATMENT-RESEARCH DICHOTOMY

One interpretation of the development and administration of Milasen is that the process is merely an example of clinical innovation similar to a new surgical technique developed in response to the unusual anatomy of a particular patient. (12) This appears to be the approach taken by European regulators, with clinicians reportedly able to request hospital ethics committee approvals to develop and administer Milasen-like interventions on a “named-patient” basis.(13) Under the umbrella of clinical medicine, such innovations are created and administered to serve the best interests of individual patients. This patient-centered focus can be contrasted with research, where there is typically said to be no expectation of direct benefit. Indeed, research participants who believe, contrary to the information they are given, that they necessarily will benefit from participation in research are said to be under a therapeutic misconception. (14)

In the Milasen case, Mila’s parents and doctors had reasons to hope for direct clinical benefit. But they also hoped that it would generate knowledge to advance a field, an understanding shared by the parents, IRB members, and clinical geneticists we interviewed about this kind of intervention, who overwhelmingly reported their hopes that such interventions would both benefit the specific patient and generate knowledge useful for others. (15) Characterizing an intervention like Milasen purely as clinical medicine would conflict with the insights of these stakeholders. It would also risk failing to record and capture adequately the knowledge gained and lessons learned from the development and administration process. A purely clinical classification could also recapitulate the ethical challenges associated with innovative surgeries and other novel clinical interventions, leaving patients potentially exposed to levels of risk that would not be tolerated in research and without independent oversight. (10)

An alternative understanding sees Milasen and similar interventions as a form of clinical research. Something approaching this position seems to be held by regulatory bodies in the U.S., which in 2021 (i.e., after the Milasen case) asserted the requirement of formal research ethics review before similar interventions are administered to patients. (16) This position also finds support in the academic literature, for example from Kane et al. who have argued that while individualized therapies “are sometimes perceived as dissolving tensions between the goals of research and care,” they should be strictly understood as a form of research. (6) On their view, the development of Milasen was clearly intended to model an approach or algorithm that, with small modifications, could be applied to other patients. “What we want to know” in a case like Milasen, they argue, “is not merely whether an individual patient benefits, but whether the intervention algorithm has potential, when applied to a series of patients, to bring about outcomes that are better than with alternative treatments.” (6) As such, they argue, the process aims to generate generalizable knowledge and therefore constitutes research. This interpretation fits with some of the goals expressed by the stakeholders we interviewed, who supported gleaning as much as possible from each individualized genetic intervention for the benefit of other patients with rare diseases. Yet the dominant approach to generalizability is not a neat fit with this kind of intervention.

Generalizability as a Value for Research

In the U.S., federal regulations define research as “a systematic investigation, including development, testing, and evaluation, designed to develop or contribute to generalizable knowledge.”(17) If a study aims at generalizable knowledge—and if human subjects are involved—the research ethics review process is triggered, which when a drug, device, or biologic is involved, in turn enables the establishment of an evidence base for FDA approval. In clinical research, knowledge is typically understood to involve information about the safety and efficacy of the intervention itself, or possibly a method for its administration. Such knowledge is “generalizable” if it has external validity—that is, if the findings apply to patients in the general population who fall under the same classification as those in the study sample. (17) To demonstrate that knowledge is generalizable, clinical research traditionally involves group comparison studies, with the randomized controlled trial (RCT) as the gold standard. A large sample can provide the necessary power to detect even a small effect, and translational medicine has diverse strategies for shaping experimental conditions to accurately represent relevant aspects of the real world.

Study designs like the RCT are not feasible when interventions are developed for a single patient, who may be the only person ever to receive the particular intervention or who may be the first of a very small number. Although development of an individualized intervention can be done systematically—e.g., according to a prospective plan that incorporates testing and evaluation to answer defined questions and assess specific outcomes—there will be no control group, or if there is, both groups will be very small. Furthermore, assessing the external validity of an intervention, already a challenge given the difficulty of reproducing the diversity of clinical populations in experimental settings, is a non-starter in individualized therapies where all, or the vast majority, of known cases are already included as subjects of the intervention. If external validity for a particular class of disease is the sole appropriate measure for assessing generalizability – and generalizability is taken to be a defining factor of research– then cases like the development and administration of Milasen will not be considered research.

But there is debate over whether external validity should be the sole or most meaningful proxy for generalizability. Some philosophers and scientists emphasize instead that small studies based on careful causal reasoning can generate valuable new knowledge by demystifying complex biological processes that cross-cut individual medical conditions. (18) For example, writing about the meaning of generalizability in the context of neurological research, Kukull and Ganguli argue that “even very narrowly defined study samples may provide widely generalizable results if conducted with an eye to rigorous internal validity,” that is, if care is taken that the study design correctly targets the variables it sets out to measure. (19) Eric Heckler and colleagues, in a paper responding to the development of personalized medicine, have called for a “small data paradigm” that can rigorously use “data by and for a specific N-of-1 unit.” (20) Although such studies may not produce generalizable knowledge in the traditional sense, Heckler and colleagues argue that knowledge capable of guiding future interventions can be generated; they call this kind of knowledge “transportable.”

Suspicion about traditional standards for establishing generalizability, and thus about traditional means of demarcating clinical research from clinical practice, is in part brought on by shifts in dominant methodologies characteristic of the precision medicine paradigm. Individualized interventions draw on the extreme ends of the spectrum, often using “big data” to discover genetic anomalies and then “small data” to test new therapeutics. They cannot appeal to traditional measures of validity that rely on an abstract disease construct. (21) As such, they challenge the traditional view that generalizability can only be assessed using external validity measures. However, there are many transferable lessons from cases like Milasen applicable to other conditions with a similar genetic cause, or where the same method of intervention delivery is being considered, or where similar methods to monitor outcomes are needed. In our empirical study of stakeholder perspectives, IRB members argued for a more expansive view of generalizability to include various types of information that could benefit unknown future patients.(15)

Expanding generalizability beyond external validity should have repercussions for the way in which studies are funded and regulated, with additional measures needed to assess their value outside the discovery context. The philosopher of medicine Lara Keuck has offered a new measure of “scope validity” to refine how we assess the potential for an experimental model to be applied to a population beyond that used for discovery. Instead of focusing on the external validity of disease constructs when evaluating the validity of biomedical results, Keuck argues, the possibility for generalizability often comes into better focus when attention is paid to the more fine-grained aspects of the experimental model and/or the patient population. Instead of offering a totalizing assessment of generalizability, then, scope validity aims to specify targets where the results of a study will be locally generalizable. In individualized therapy studies, where disease constructs are often irrelevant given the uniqueness of patients’ conditions, external validity with respect to a general patient population is most likely irrelevant, and critical attention to scope becomes crucial. For example, in the Milasen case, an assessment of scope validity might focus attention on the potential for aspects of that drug’s development pathway to be generalized to other therapeutic targets with similar, but not identical, characteristics. As Keuck notes, a consideration of scope validity could estimate the extent to which the development of an experimental drug with no immediate transformative effects on healthcare nonetheless might serve medicine’s general aim of being useful for the many, not just the few.

MILASEN AS A RESEARCH-TREATMENT HYBRID

Because Milasen and other individualized interventions have features of both clinical research and innovative treatment, Bateman-House and Kearns have described them as a “troublesome, liminal category” that “blurs to the point of erasing the historically distinct line separating research from treatment.” (5) One response to this mixed character would be to understand individualized interventions as combining research and clinical innovation in a stepwise fashion, with the interventions initially considered research, but then switching to innovative clinical care prior to administration in patients. This approach in some sense captures the regulatory and oversight approaches applied to the Milasen case itself, however it creates an arbitrary break in the process that does not cohere with the reported experience of the patient’s family or her clinicians. Further, it would counterintuitively result in research-level protections for the low-risk cell collection step, but not for the riskier intervention administration step.

Instead, we propose that development and administration of Milasen and other individualized genetic interventions be recognized as both research and treatment—that is, as research-treatment hybrids (see Figure 1). This hybridity may come through in the aims of each intervention, which might simultaneously include the production of generalizable knowledge and benefiting the patient therapeutically; their methods, which might draw on traditional study designs as well as clinical care protocols; their funding, which might be provided by designated research dollars and clinical care payment mechanisms such as insurance or patient’s own funds; and their ethics and oversight, which might involve IRBs applying the rules of human subjects research and clinical ethics services navigating the ethics of clinician-patient relationships.

Recognizing Milasen and similar interventions as research-treatment hybrids is descriptive rather than prescriptive; we believe that individualized genetic treatment studies have already, implicitly, taken this form. Nevertheless, our account has normative implications; chiefly that it more accurately reflects key stakeholders’ therapeutic and knowledge generation goals. In our interviews with family members of children with rare genetic disorders, geneticists, and IRB members, we explicitly asked them whether they understood these novel individualized interventions to be research or treatment, and most reported that they were both. (15) Families in particular found the question odd, emphasizing both their desire to help their child and the hope that knowledge learned could help others. These results support hybridity as a description, and descriptive accuracy in turn increases the likelihood that those directly involved in development and administration will recognize their own experience in the language used to describe these interventions, as well as in the ethical and regulatory tools supporting their use.

We should expect that this hybridity will take a different form in each case; individualized genetic interventions form a heterogenous class. Accordingly, this analysis does not amount to an evasion of the challenge of sorting out what individualized genetic treatments are by merely answering “both.” The regulatory and ethical challenges that characterize this class should be met by establishing the unique hybrid nature of each case. If, as we suspect, individualized interventions vary in the research and clinical aspects they assume, there may be no simple answer to how they should be funded, overseen, and regulated; such decisions will need to be taken on a case-by-case basis. At the same time, recognizing them as aggregates of research and clinical paradigms, rather than new and emergent sorts of studies, should enable patients, clinicians, researchers, institutions, and regulators to draw on the best of both paradigms to better understand and address the ethical and legal questions these interventions raise, preserving the foci of clinical ethics (patient centeredness, an emphasis on communication and compassion, and the involvement of family) while incorporating protections from research oversight (see Figure 2).

FIGURE 2:

Potential oversight and ethics implications of hybridity

Regarding expectations of benefit, for example, hybridity validates the clinical ambitions of providers and the therapeutic expectations of patients and families. Similarly, hybridity allows for the expectation that patient selection will be driven by clinical judgment: patients are selected based at least in part on the hope that they will benefit. Hybridity also recognizes and perhaps even validates the dual roles of clinician-researchers who, like Yu, are involved in care of the patient and design and administration of the individualized therapy. Recognizing these roles does not mean throwing out traditional research-related precautions: there may still be a need for a research-only or independent colleague familiar with the condition and risks and benefits of the therapy to obtain informed consent, for example. Instead, it serves to highlight non-judgmentally the inevitable tensions and complexities that can face the clinician-researcher and to introduce a mix of mechanisms for managing them.

That said, hybridity does introduce complications. Consent processes may become more detailed when they must acknowledge patients’ and families’ expectations of benefit, while also emphasizing uncertainty of response, novelty, and risk. There may be heightened risk that the research nature of the protocols will be downplayed or not sufficiently appreciated by patients who are focused on the therapeutic prospects. Oversight may also be more burdensome if studies need to undergo both research and clinical ethics review. One response might be to develop a form of specialized review that combines both approaches. Indeed, where cases share complex scientific or clinical features, there might be value in a specialized national review group. At this time, the FDA has made clear that it expects IRB review of these cases, a requirement that perhaps reflects the agency’s understanding that some IRBs might think individualized therapies do not meet the legal definition of research—regardless, the FDA wants to see research-level protections.

Regarding funding, categorizing the development and administration of at least some individualized therapies as a type of research may open access to public research funds. This would be a welcome development for patients and families who are otherwise left to raise these funds themselves. We note, however, that while the development and administration of individualized therapies like Milasen might count as research, this does not settle questions about the value of their development when compared with other possible uses of limited research funds. Genomics in general, and precision medicine in particular, receive extensive criticism on healthcare equity and distributional justice grounds that can only be partially addressed by reference to the generalizable knowledge these activities might generate. (22)(23)(24)(25)ⁱⁱ At least initially, individualized genetic therapies are likely to benefit disproportionately already advantaged individuals who can participate in such studies. That said, recognizing that some such studies have broader scope could demonstrate how their development might attenuate these inequalities.

CONCLUSION

The Milasen case is an example of a research-treatment hybrid: an individualized genetic intervention that was both designed to benefit a particular patient and intended to generate knowledge that can be applied to other patients with different genetic conditions. It was a case driven by clinical judgment and shaped by clinical ethics—a case where clinicians worked to relieve suffering through the development and administration of a novel therapy that they, and the patient’s family, very much hoped would provide direct benefit. It was also a case driven by the search for scientific knowledge and shaped by research ethics and research regulations. Milasen represents, therefore, not only a milestone in precision medicine but a chance to enrich our understanding of what is considered research, and what types of knowledge gains can come from different intervention development pathways.